Many drugs are administered by injection because other methods of administration do not provide acceptable drug delivery. Many drugs, such as insulin, cannot be taken orally because they are inactivated in the digestive track. For example, insulin has been administered traditionally by subcutaneous injection in order to attain the needed drug bioavailability. One disadvantage of subcutaneous drug administration is that many patients are reluctant or unable to give themselves infections several times a day. Other disadvantages of subcutaneously injected drugs, include great intraindividual variability of absorption (See e.g., Berger, M. et al., in Sayler, J. S. ed. Insunn. update: 1982 Amersterdam Excerpta Medica, 1982, 97-110; Galoway, J. A. et al., Diabetes Care (1981), 4:366-76) and absorption at too slow a rate to provide rapid onset and short duration of drug action. Nasal administration of drugs offers advantages over subcutaneous administration in terms of rate of absorption as well as of convenience. Thus, the nasal route for drug administration is of great interest.
Drugs are often poorly absorbed through the nasal mucosa and thus administration by, e.g., a nasal spray, typically requires larger amounts of the drug than administration by injection. Various methods have been tried to enhance absorption of drugs across nasal membranes. For example, U.S. Pat. No. 4,476,116 discloses polypeptide containing pharmaceutical formulations having chelating agents which enhance peptide absorption across nasal mucous membranes.
Several investigators have demonstrated that insulin can be delivered across the nasal mucosa in biologically active doses (Major, R. H., J. Lab. Clin. Med. (1935), 2, 278-80; Hanxiss J. et al., Acta. Med. Acad. Sci. Hung (1958), 12, 107-14; Hirai S. et al., Diabetes (1978), 27, 296-9; Hirata Y. et al., Amsterdam: Excerpta Medica International Congress Semes. 1979, 468, 319-26; Pondroli A. E. et al., Br. Med. J. (1982) 284, 303-6; Moses, A. C. et al., Diabetes (1983) 32, 1040-7). Aside from its convenience, nasally administered insulin is absorbed rapidly by the nasal mucosa, mimicking more closely the insulin response to a meal seen in normal persons.
Compositions which can be utilized to improve the absorption of nasally administered drugs with reduced nasal irritation, especially when used with chronically administered drugs, are desirable.
The utilization of certain surface-active agents to enhance the absorption of insulin has been demonstrated. Hirai and coworkers (Hirai, S. et Intl. J. Pharmaceutics (1981) 1, 173-184; G.B. Patent specification 1 527 605) have shown enhanced absorption of nasally administered insulin in rats by the use of surface-active agents such as laureth-9. Salzman and coworkers have demonstrated enhanced absorption of nasally administered insulin in humans using laureth-9 (Salzman, R. et al., N.E. J. Medicine, 1985 April, 1078-1084) but found that such administration was often accompanied by nasal irritation such as stinging, congestion and rhinorrhea, predominantly due to the surfactant laureth-9, and that such effects were proportional to the concentration of laureth-9.
Although laureth-9 administered nasally at 0.1% by weight, was tolerated by all subjects tested by Salzman (Salzman et al., supra), it was found that 0.1% laureth-9 was only moderately effective in promoting insulin absorption.
Thus, although intranasal administration of drugs is a potentially useful method of administration, compositions which enhance absorption through the nasal mucosa with reduced irritation are desirable.